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Biomedical subjects

George M Simpson

Publications and source records attributed to George M Simpson.

At least 19 recordsLinked to original sources
PubMed2007

Weight gain during a double-blind multidosage clozapine study.

Possible variables associated with weight gain during clozapine treatment include dosing, treatment duration, baseline body mass index (BMI), sex, and plasma norclozapine concentrations. Weight gains during a double-blind, randomized clozapine study using 100-, 300-, and 600-mg/d doses were analyzed. It was hypothesized that weight gain was associated with baseline BMI, clozapine dosing, and demographic factors. The possible contribution of plasma clozapine and norclozapine concentrations was explored. Fifty treatment-refractory schizophrenia patients were randomized to 100-, 300-, or 600-mg/d doses of clozapine for a 16-week, double-blind treatment in a research ward. Nonresponsive patients went onto a second and/or a third 16-week, double-blind treatment at the other doses. Weights of patients were measured every week. During the first clozapine treatment, weight gain varied across 3 baseline BMI categories (normal-weight patients [4.1 kg, P < 0.001], overweight patients [2.6 kg, P = 0.05], and obese patients [0.36 kg, not significant]) and according to dosing (600 mg/d [4.4 kg], 300 mg/d [2.6 kg], and 100 mg/d [1.3 kg]). Sex had no effect after controlling for baseline BMI and dose, but the African-American race had a strong significant effect despite the small number of African Americans (n = 6). At the end of the first clozapine treatment, plasma norclozapine concentration was not significantly correlated with weight gain in the total sample (r = 0.16, P = 0.32, n = 43), but seems to be strongly correlated in nonsmokers. Despite its limitations, this study indicates that baseline BMI, dosing, and, possibly, the African-American race may be major determinants of clozapine-induced weight gain.

Antipsychotic Agents↗
PubMed2006

Review of antipsychotics in children and adolescents.

The use of antipsychotics in children and adolescents in the clinical setting is increasing. This article reviews 77 clinical trials published in the last 10 years, investigating their efficacy, effectiveness, safety and pharmacokinetic data in paediatric populations. The diagnostic categories in which the antipsychotics are commonly used (schizophrenia, pervasive developmental disorders, Tourette's disorder, mental retardation/subaverage intelligence, mood disorders and disruptive behaviour disorders) were used in order to review the evidence and effectiveness. All randomised, double-blind, placebo-controlled trials from the past decade are also summarised. This review refers to recent relevant practice parameters, guidelines and reviews throughout the text. Consistent with previous reviews, it is concluded that the recent trend of increased use of antipsychotics in children and adolescents is not adequately supported by evidence. Specific suggestions have been provided on how to incorporate the existing evidence base into clinical decision making. The review ends with the authors' opinion on the clinical and research implications for the field and future directions.

Adolescent↗
PubMed2006

A 1-year double-blind study of 2 doses of long-acting risperidone in stable patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the effects of 2 doses of long-acting risperidone injection in patients with schizophrenia or schizoaffective disorder. METHOD: This 52-week, prospective, randomized, double-blind, multicenter, international study included clinically stable outpatients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Settings included physicians' offices and clinics. Patients received a fixed dose of long-acting risperidone (25 or 50 mg) every 2 weeks. Primary outcome was time to relapse, defined as either re-hospitalization or other exacerbation criteria. Other assessments included the Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness scale, and functional and quality-of-life measures. Safety was assessed via treatment-emergent adverse events, laboratory tests, and movement disorder rating scales. Data were collected from December 2002 to September 2004. RESULTS: A total of 324 patients were randomized to 25 mg (N = 163) or 50 mg (N = 161) of long-acting risperidone. Time to relapse was comparable (p = .131) for both groups. Projected median time to relapse was 161.8 weeks (95% CI = 103.0 to 254.2) with 25 mg and 259.0 weeks (95% CI = 153.6 to 436.8) with 50 mg. One-year incidences of relapse were 21.6% (N = 35) and 14.9% (N = 24), respectively (p = .059). Psychiatric hospitalization was the reason for relapse for 16 (10%) in the 25-mg group and 10 (6%) in the 50-mg group. Patients experienced statistically significant but modest improvements at endpoint in most measures (i.e., psychotic symptoms, functioning, movement disorder severity) with both doses, with no significant between-group differences. CONCLUSION: In this 1-year study, long-acting risperidone was associated with low relapse and rehospitalization rates, indicating that doses of 25 to 50 mg are appropriate for long-term treatment in schizophrenia.

Adult↗
PubMed2005

Plasma clozapine concentration coefficients of variation in a long-term study.

Kurz et al. conducted the first study of the intra-individual variability of clozapine plasma concentrations but did not take into account the effect of smoking and co-medication. As patients were receiving varying doses, Kurz et al. standardized plasma levels by using a plasma level/dose/kg ratio. In 15 patients, the mean coefficient of variation (CV) was 53% (S.D. = 21). In this new study, plasma clozapine and norclozapine concentrations were measured every 2 weeks in 47 patients randomized to 100, 300, or 600 mg/day for 16-week double-blind clozapine trials under controlled conditions (stable smoking, limited co-medication and absence of caffeinated beverages). For 100, 300 and 600 mg/day, the respective mean CVs for plasma clozapine concentrations were 23% (S.D. = 14), 19% (S.D.= 11) and 18% (S.D. = 8). For the combined concentrations of clozapine and norclozapine, the respective mean CVs were 20% (S.D. = 13), 16% (S.D. = 9) and 15% (S.D. = 7). Under 100 mg/day, the mean CV for clozapine concentrations was significantly higher for heavy smokers than non-heavy smokers (32%, S.D. = 3 vs. 19%, S.D. = 8) (p = 0.03). Studies of CVs in other environments are needed. Clozapine CVs may be important in order to understand the importance of variations around the therapeutic range and to interpret drug interactions above the usual noise of measuring plasma concentrations.

Adult↗
PubMed2005

Does clozapine decrease smoking?

McEvoy et al.'s study in 1999, which used cotinine levels but had limited power, suggested that clozapine treatment may be associated with a mild smoking decrease (particularly when plasma clozapine levels are > 150 ng/ml). Some naturalistic studies also suggest that clozapine treatment may be associated with a mild smoking decrease. The present study included 38 schizophrenic daily smokers from a double-blind clozapine trial. Five analyses were tested for significant decreases in plasma cotinine levels from a haloperidol baseline to: (1) the end of clozapine trials regarding clozapine doses (100, 300 or 600 mg/day), (2) the end of the clozapine trial where the highest plasma clozapine level was achieved, (3) the end of the clozapine trial where a clozapine level in the 150-450 ng/ml range was achieved, (4) the end of the first clozapine trial regardless of clozapine dose, and (5) the end of the last clozapine trial in the study. The first and straightforward analysis by dose showed no clozapine effects on smoking. The second and the third analyses (an attempt to mimic the design by McEvoy et al. [McEvoy, J.P., Freudenreich, O., Wilson, W.H., 1999. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol. Psychiat. 46, 125-129.]) also indicated that there was not a significant effect of clozapine on smoking. The fourth and five analyses were also negative. None of the five analyses in our clozapine trial demonstrated that clozapine had major effects on smoking. This study cannot rule out that in some subjects, clozapine treatment may be associated with a small decrease in smoking. New prospective longitudinal studies using repeated cotinine and clozapine levels are needed to explore whether clozapine may reduce smoking in some patients.

Adult↗
PubMed2005

Six-month, blinded, multicenter continuation study of ziprasidone versus olanzapine in schizophrenia.

OBJECTIVE: The authors' goal was to compare the efficacy and tolerability of 6 months' treatment with flexible-dose ziprasidone and olanzapine in patients with schizophrenia or schizoaffective disorder. METHOD: Brief Psychiatric Rating Scale (BPRS) scores and Clinical Global Impression (CGI) severity scores were obtained for 126 responders to a 6-week acute study of olanzapine and ziprasidone during a blinded 6-month continuation study and optional extension study. RESULTS: Comparable improvements in BPRS and CGI severity scores were seen with both drugs. Olanzapine produced significant increases from acute-study baseline values in weight and body mass index and within-group increases in total cholesterol, low-density lipoprotein cholesterol, and fasting insulin. Between-group differences were not significant for lipids and insulin. Mean QTc values at endpoint were 407.1 msec (baseline mean=406.0 msec) and 394.4 msec (baseline mean=399.7 msec) for ziprasidone and olanzapine, respectively. No patient had a QTc interval > or =500 msec. CONCLUSIONS: Ziprasidone and olanzapine had comparable long-term efficacy; olanzapine was associated with significant weight gain and metabolic alterations.

Ambulatory Care↗
PubMed2005

An 8-week open-label trial of a 6-day course of mifepristone for the treatment of psychotic depression.

OBJECTIVE: Several investigations suggest that mifepristone leads to the rapid amelioration of psychotic depression. However, these studies were of short duration (1 week or less) and included subjects who were taking other psychotropic medications. The goals of this study were to extend these findings by conducting an 8-week trial of mifepristone for subjects with psychotic depression who were taking no concomitant psychiatric medications. METHOD: Twenty subjects with a DSM-IV major depressive episode with psychotic features (for convenience we use the term psychotic depression) taking no psychotropic medications were given a 6-day course of mifepristone and followed as inpatients for a total of 8 weeks. Nonblinded ratings using the Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impressions scale (CGI) were performed at baseline and at the end of weeks 1, 4, and 8. The Brief Psychiatric Rating Scale (BPRS) was also administered at baseline and after weeks 4 and 8. Subjects were recruited between February 2003 and December 2003. RESULTS: Significant improvements in HAM-D and CGI scores were shown after 1 week and between weeks 1 and 4 but not between weeks 4 and 8. BPRS scores improved significantly after week 4, while the improvement in BPRS scores between weeks 4 and 8 was of borderline significance. CONCLUSION: Mifepristone appears to be a useful intervention for psychotic depression, leading to significant improvements even after a 1-week course of administration. Issues related to its optimal dosing and to prediction of response are discussed, as are the implications of lack of a placebo group and the use of nonblinded ratings in the present study.

Adolescent↗
PubMed2005

Atypical antipsychotics and the burden of disease.

The atypical antipsychotics are defined by improved tolerability in comparison with conventional antipsychotics. Specifically, the atypicals are substantially less likely to cause troubling extrapyramidal symptoms and prolactin elevation. This reduction in adverse effects (AEs) is attributed to their short duration of occupancy at dopamine-2 receptors in the central nervous system and a high degree of activity at serotonin receptors of various subtypes. The main AEs associated with the atypicals are weight gain and metabolic effects, including disturbances in glucose metabolism and a risk of induced diabetes. However, the atypicals are not interchangeable: the risk of incurring these effects is high with clozapine and olanzapine, moderate with risperidone and quetiapine (but perhaps increasing at higher doses), and minimal with ziprasidone and aripiprazole. The atypicals have proved useful as monotherapy in treating schizophrenia and in combination with other psychoactive agents in treating bipolar disorder. Because of their improved tolerability, the atypicals offer the prospect of improved compliance and reduced risk of relapse, thus decreasing costs by the need for less hospitalization.

Antipsychotic Agents↗
PubMed2004

Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia.

OBJECTIVE: To assess changes in cognitive function in stable outpatients with schizophrenia switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or poor tolerability. METHODS: In three separate 6-week trials, patients received ziprasidone 40 mg b.i.d. for 2 days, followed by 20-80 mg b.i.d. for the next 40 days. Before switching, and at endpoint, patients were evaluated with tests of working and secondary verbal memory, vigilance, visuomotor speed, verbal fluency, and executive functioning. Principal components factor analysis was performed to test for clustering of cognitive variables. RESULTS: Significant improvements were seen at endpoint in secondary verbal memory (in all three groups), vigilance (in patients switched from conventional antipsychotics or risperidone), executive function (in patients switched from conventional antipsychotics or risperidone), and verbal fluency. Factor analysis on baseline scores suggested reduction of the cognitive variables to three factors: verbal skills, attention and short-term memory, and executive functioning. Analysis of z-transformed mean change in factor scores showed significant improvement in verbal skills and global score following the switch from conventional antipsychotics, olanzapine, or risperidone. CONCLUSIONS: Patients requiring a change in antipsychotic therapy may exhibit cognitive improvement following a switch to ziprasidone.

Adolescent↗
PubMed2004

Possible individual and gender differences in the small increases in plasma prolactin levels seen during clozapine treatment.

In vitro, animal studies and acute short-term clinical studies suggest clozapine releases prolactin but the effect is much smaller than that of typical antipsychotics. Repeated early morning trough measures of plasma clozapine and prolactin levels on each subject were studied during the course of a double-blind dose-response clozapine study. After a 4-week 10 mg/day haloperidol trial and a one-week washout, treatment- refractory schizophrenics were successively randomized to 100, 300,or 600 mg/day of clozapine for a 16- week treatment. The statistical analyses included 35 subjects (19 females and 16 males). The within-subject correlation of prolactin levels was 0.32 with clozapine levels and 0.75 with haloperidol levels. An increment of 100 ng/ml in clozapine level yielded an average increment of 0.45 ng/ml of prolactin levels in females and of 0.15 ng/ml in males. An increment of 1 ng/ml in haloperidol level yielded an average increment of 2.6 ng/ml of prolactin levels in females and of 1.5 ng/ml in males. At least one fourth of patients demonstrated a significant and strong (r > 0.6) correlation between clozapine and prolactin levels. This study suggests that clozapine has effects on prolactin levels but effects are small and may be more evident in some individuals, particularly females.

Adult↗
PubMed2004

Haloperidol half-life after chronic dosing.

In normal subjects after a single oral dose, haloperidol half-life has been reported to range 14.5-36.7 hours (or up to 1.5 days). After chronic administration, half-lives of up to 21 days have been reported. The objective of this study was to evaluate specific factors that might account for differences in haloperidol half-life in patients taking haloperidol chronically, including gender, age, weight, race, CYP2D6 and CYP3A5 genotypes, comedication, and smoking.Thirty-one patients were administered haloperidol for 4 weeks followed by a 1-week washout before administration of clozapine. Haloperidol plasma levels were measured weekly for at least 2 months after discontinuation. The geometric mean for haloperidol half-life and detectable levels duration were 3.9 and 13.8 days, respectively. Within 31 subjects, 58% (18/31) had half-lives <3 days (1.2-2.3 days) and 42% (13/31) had half-lives > or =3 days. Two of 3 patients with half-lives longer than 30 days (720 hours) and levels detectable >2 months had received haloperidol decanoate. Five patients who received haloperidol decanoate in the prior year were excluded from a comparison between patients with long haloperidol half-lives (> or =3 days, n = 10) and patients with short half-lives (<3 days, n = 16). The only significant difference between the two groups was that African-Americans (n = 4) were all found to have a long haloperidol half-life (P = 0.014). CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days. This study suggests that haloperidol half-life following repeated drug administration is substantially more prolonged than what has been observed after acute haloperidol administration.

Adult↗
PubMed2004

Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder.

OBJECTIVE: Limited randomized, controlled trial data exist on possible differences between atypical antipsychotics in efficacy, overall tolerability, and important indices of health status. The authors compared the efficacy and tolerability of ziprasidone and olanzapine in the treatment of acutely ill inpatients with schizophrenia or schizoaffective disorder. METHOD: In this 6-week, multicenter, double-blind, parallel-design, flexible-dose trial, patients were randomly assigned to receive ziprasidone (N=136) or olanzapine (N=133). Primary efficacy measures were improvement in Brief Psychiatric Rating Scale and Clinical Global Impression (CGI) severity scale scores; secondary measures were scores on the CGI improvement scale, Positive and Negative Syndrome Scale, and Calgary Depression Scale for Schizophrenia. Tolerability assessments included fasting lipid profiles, fasting glucose and insulin measurements, electrocardiography, and monitoring of vital signs and body weight. RESULTS: The overall mean daily doses were 129.9 mg (SD=27.3) for ziprasidone and 11.3 mg (SD=2.8) for olanzapine. Both antipsychotics were efficacious in improving symptoms and global illness severity. The two treatment groups did not differ significantly in primary or secondary efficacy measures at endpoint or in by-visit analysis. Both agents were well tolerated. Body weight, total cholesterol, triglycerides, and low-density lipoprotein cholesterol significantly increased with olanzapine but not with ziprasidone; all between-group comparisons of these variables were significant and favored ziprasidone. Olanzapine, but not ziprasidone, was associated with significant increases in fasting insulin level. No patient in either group exhibited a corrected QT interval >/=500 msec. CONCLUSIONS: During 6 weeks' treatment, ziprasidone and olanzapine demonstrated comparable antipsychotic efficacy. Differences favoring ziprasidone were observed in metabolic parameters.

Adolescent↗
PubMed2003

The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development.

The National Institute of Mental Health initiated the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program to evaluate the effectiveness of antipsychotic drugs in typical settings and populations so that the study results will be maximally useful in routine clinical situations. The CATIE schizophrenia trial blends features of efficacy studies and large, simple trials to create a pragmatic trial that will provide extensive information about antipsychotic drug effectiveness over at least 18 months. The protocol allows for subjects who receive a study drug that is not effective to receive subsequent treatments within the context of the study. Medication dosages are adjusted within a defined range according to clinical judgment. The primary outcome is all-cause treatment discontinuation because it represents an important clinical endpoint that reflects both clinician and patient judgments about efficacy and tolerability. Secondary outcomes include symptoms, side effects, neurocognitive functioning, and cost-effectiveness. Approximately 50 clinical sites across the United States are seeking to enroll a total of 1,500 persons with schizophrenia. Phase 1 is a double-blinded randomized clinical trial comparing treatment with the second generation antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone to perphenazine, a midpotency first generation antipsychotic. If the initially assigned medication is not effective, subjects may choose one of the following phase 2 trials: (1) randomization to open-label clozapine or a double-blinded second generation drug that was available but not assigned in phase 1; or (2) double-blinded randomization to ziprasidone or another second generation drug that was available but not assigned in phase 1. If the phase 2 study drug is discontinued, subjects may enter phase 3, in which clinicians help subjects select an open-label treatment based on individuals' experiences in phases 1 and 2.

Adolescent↗
PubMed2003

Serum antimuscarinic activity during clozapine treatment.

This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics. In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders. Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.

Antipsychotic Agents↗